CN104193660B - Substituted 1,3- diphenyl propane derivatives, their preparation and purposes - Google Patents

Substituted 1,3- diphenyl propane derivatives, their preparation and purposes Download PDF

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CN104193660B
CN104193660B CN201410016196.3A CN201410016196A CN104193660B CN 104193660 B CN104193660 B CN 104193660B CN 201410016196 A CN201410016196 A CN 201410016196A CN 104193660 B CN104193660 B CN 104193660B
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J-F·德洛梅尔
R·汉夫
K·科蒙-贝特朗
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Genfit SA
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Abstract

The present invention relates to substituted 1,3 diphenyl propane derivative, their preparation and purposes, especially in human and animal's health field.

Description

Substituted 1,3- diphenyl propane derivatives, their preparation and purposes
The application is to submit on June 21st, 2007, entitled " substituted 1,3- diphenyl propane derivatives, it Preparation and purposes " Chinese patent application 200780030962.X divisional application.
The present invention relates to substituted 1,3- diphenyl propane derivatives, the pharmaceutical composition comprising them and their treatments Purposes, especially in human and animal's health field.
Astoundingly, present inventor have demonstrated that the compound of the present invention has inherent PPAR agonist characteristics.
Therefore, heretofore described molecule is in treatment metabolic syndrome complication, insulin resistance, diabetes, blood fat Exception, atherosclerosis, angiocardiopathy, obesity, hypertension, inflammatory disease（Asthma etc.）, neurodegenerative disease（A Er Thatch sea Mo's disease etc.）, cancer etc. and in terms of reducing overall risk it is particularly interesting.The compound of the present invention is preferred for Treat dyslipidemia.
Diabetes, obesity and dyslipidemia（High plasma LDL-cholesterol and triglyceride levels, low HDL-cholesterol water Equality）It is the cardiovascular risk factors that some are clearly identified, they make one to be easy to suffer from angiocardiopathy（Mensah M, 2004）.Life style risk factors are also contemplated that, such as use tobacco, the life style of sitting and unbalanced diet.These Factor has synergistic effect：These several factors exist simultaneously the risk for dramatically increasing cardiovascular disease.Therefore, angiocardiopathy Overall risk is worth inquiring into.2004, dyslipidemia prevalence rate reached the 43.6% of population in industrialized country.Diabetic The prior factor for just making diabetes become cardiovascular epidemiology at present that increases sharply：It is estimated that by 2010, 7.6% population will become diabetic（Fox-Tucker J,2005）.
According to international atherosclerosis association（International Atherosclerosis Society, 2003）, Angiocardiopathy is the main cause of death of industrialized country and just becomes more universal in developing country.Main painstaking effort Pipe disease is heart disease, cerebral ischemia and peripheral arterial disease.
Therefore, these data proof should take effective measures to significantly decrease cardiovascular morbidity and incidence, and Disclose the necessity for finding effective therapy and Binding change life style.Consider suffer from angiocardiopathy risk factors and Their consequence, this is mondial emergency.
Because of the PPAR agonist characteristics of the compound of the present invention, they with lipid and/or abnormal carbohydrate metabolism phase The disease of pass（pathologies）Treatment and reduction such as diabetes, obesity, dyslipidemia or inflammation is cardiovascular overall It is particularly interesting in terms of risk.
Known PPARs（α, γ and δ）It is related to this kind of disease（Kota BP et al., 2005）：Therefore, on ligand and receptor City is to treat these diseases（Lefebvre P et al., 2006）, and various selective or non-selective PPAR is adjusted Agent, agonist or antagonist are currently under in high level of development.To insulin resistance, obesity, dyslipidemia, hypertension And/or there is inflammation the PPAR conditioning agents of advantageous effect can be used for metabolic syndrome（Or X syndrome）Treatment（Liu Y and Miller A,2005）.
PPAR families include three kinds of hypotypes, referred to as α, γ and δ（Also referred to as β）, the different gene code of each freedom.These by Body belongs to nuclear receptor and transcription factor superfamily, they connect with certain aliphatic acid and/or their lipid metabolite It is activated when tactile.The PPAR of activation and 9-cis-retinoic acid receptor（RXR or class visual yellow X receptors）Formed heterodimer and with The particular responses element of target gene promoters（PPRE or peroxisome proliferation response element）In conjunction with thus offer turns Record control.
PPAR α controls（Liver and muscle）The homeostasis of lipid-metabolism and glucose is related to by directly controlling coding And the transcription of the gene of the protein of lipid homeostasis influences the metabolism of lipid within endothelial cells and carbohydrate, has anti-inflammatory and anti-increasing Grow effect, and the atharosclerosis effect for preventing cholesterol from being accumulated in macrophage by stimulating Cholesterol Efflux （Lefebvre P, Chinetti G, Fruchart JC and Staels B, 2006）.Fibrates（Fenofibrate, Bezafibrate, Ciprofibrate, Gemfibrozil）It is used for clinical medicine by PPAR α, by reducing triglycerides and improving HDL（High density lipoprotein level In vain）Level treats certain dyslipidemias.
PPAR γ are adipogenic key regulators.Moreover, it participates in lipid-metabolism, the glucose of mature fat cell Homeostasis, particularly insulin resistance, inflammation, Macrophage cholesterol accumulation and cell Proliferation（Lehrke M and Lazar MA, 2005）.Therefore, PPAR γ work in the pathogenesis of obesity, insulin resistance and diabetes.Thiazolidinedione Class（Rosiglitazone, troglitazone etc.）It is the PPAR γ ligands for treating type-2 diabetes mellitus.
It there is now PPAR 2-delta ligands（L-165041, GW501516 are in clinical development at present）, but currently without PPAR 2-delta ligands are used as drug.However, this receptor be exploitation for treat dyslipidemia, atherosclerosis, obesity and The attractive target of the available drug of insulin resistance：PPAR δ actually participate in lipid and carbohydrate metabolism Control, energy balance, neurodegeneration, obesity, the formation of macrophage foam cells and inflammation（Gross B et al., 2005）.
In addition to PPAR ligands directly act on the adjusting of lipid and carbohydate metabolism, these molecules because PPAR target gene Extremely diversity and with pleiotropism action spectrum.These multiple properties make PPAR become to treating following disease and reducing overall The interesting therapy target of risk：Atherosclerosis, cerebral ischemia, hypertension, disease related with neovascularization （Retinopathy, diabetes etc.）, inflammation and autoimmune disease（Crohn disease, psoriasis, multiple sclerosis, asthma etc.）、 Neoplastic disease（Carcinogenesis etc.）, neurodegenerative disease, with the relevant complication of metabolic syndrome, insulin resistance, diabetes, blood fat Exception, angiocardiopathy, obesity etc..
Because of the PPAR agonist characteristics of the compound of the present invention, they are for improving and lipid and/or carbohydate metabolism The especially treatment of dyslipidemia of abnormal relevant disease and the advantageous treatment tool for reducing cardiovascular overall risk.
More generally, by acting on several adjustment processes simultaneously, the compound of the present invention is for treating following disease And reduce the favourable therapeutic means of overall risk：Complication related with metabolic syndrome（It is characterized in that fat, particularly abdomen Fat, the abnormal serum lipid concentrations in portion（High triglyceride level and/or low HDL cholesterol levels（Dyslipidemia））, blood glucose rise And/or insulin resistance and hypertension）, atherosclerosis, angiocardiopathy, insulin resistance, obesity, hypertension, sugar Urinate disease, dyslipidemia, angiocardiopathy, inflammatory disease（Asthma etc.）, neurodegenerative disease（Alzheimer's disease etc.）, cancer Deng.
The present invention relates to the compounds derived from 1,3- diphenyl propane derivative compounds, with following general formula：
Wherein：
X1 represents R1 G1-R1 groups；
X2 represents halogen atom, R2 G2-R2 groups；
X3 represents R3 G3-R3 groups；
X4 represents halogen atom, R4 G4-R4 groups；
X5 represents R5 G5-R5 groups；
R1 represents hydrogen atom or non-halogenated alkyl；
R2 represents hydrogen atom or non-halogenated alkyl；
R3, R4 are identical or different with R5, represent hydrogen atom or by one or more group 1 or group 2 substituent groups substitution Alkyl or unsubstituted alkyl；
G1, G2, G3, G4 are identical with G5 either different to represent oxygen atom or sulphur atom；
Either at least one group is corresponding with R3, G3R3, R4, G4R4, R5 or G5R5 formula in X5 by X3, X4, wherein：
G3, G4 and G5 as described above, and
R3, R4 are identical or different with R5, represent the alkyl by one or more group 1 or group 2 substituent groups substitution；
A is represented：
(i) CR6R7 groups, wherein：
R6 and R7 it is identical it is either different represent hydrogen atom, hydroxyl, alkyl or-OR8 groups,
R8 is defined as follows,
(ii) carbonyl (CO),
(iii) oximido (C=N-O-H) or oxime ether (C=N-O-R8),
R8 is represented by the aryl alkyl that either naphthenic base replaces or unsubstituted alkyl；
D is represented：
(i) carbon atom (CH being connect with two hydrogen atoms2),
(ii) it is connect with both hydrogen atom and G2 to form oxidation or vulcanize the carbon atom of heterocycle；
1 substituent group of group is selected from-COOR9 and-CONR9R10；
2 substituent groups of group are selected from-SO3H and-SO2NR9R10；
R9, R10 are identical or different with R5, represent hydrogen atom or by least one group 1 or group 2 substituent groups substitution Alkyl or unsubstituted alkyl；
Other than leading to the compound of formula (I) as follows：A representatives-CR6R7 groups in the compound, R6 and R7 represent hydrogen Atom, and at least Three Represents hydrogen atom in group X1, X2, X3, X4 and/or X5 in the compound；
Its pure stereoisomers（Diastereoisomer, enantiomter）Or mixing stereoisomer, racemic mixing Object, geometric isomer, tautomer, salt, hydrate, solvate, solid form and their mixture.
Within the scope of the invention, term " alkyl " refer to saturation, straight chain, branch be either cricoid, halogenated or non-halogen The alkyl in generation, the especially alkyl with the carbon atom of 1-24, preferably 1,2,3,4,5,6,7,8,9 or 10, such as methyl, three Methyl fluoride, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, neopentyl, n-hexyl or Cyclohexyl.
Term " naphthenic base " refers to alkyl as defined above and forms at least one ring（Such as with 3-8 carbon atom Naphthenic base：Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and cyclooctyl）.
Term " alkoxy ", which refers to, passes through oxygen atom（Ehter bond）Mode be connected to the alkyl chain on molecule.The alkyl chain pair It should be in above-mentioned definition.Available example is methoxyl group, trifluoromethoxy, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen Base, isobutoxy, tert-butoxy, sec-butoxy or hexyloxy.
Term " aryl " refers to the aromatic group for preferably comprising 5-14, advantageously comprising 6-14 carbon atom, may be inserted into One or more is selected from the hetero atom of N, O, S or P（More specifically it is known as " heteroaryl "）.They are typically monocycle or double Ring, and 6-14 carbon atom is advantageously comprised, such as phenyl, Alpha-Naphthyl, betanaphthyl, anthryl or fluorenyl.
Referring to insertion, one or more is selected from the heteroatomic as defined above of O and S to term " oxidation or vulcanization heterocycle " Naphthenic base.Adducible example has thiapyran or pyrans.
Halogen atom is understood to bromine atom, chlorine atom, fluorine atom or iodine atom.
Non-halogenated alkyl is the alkyl as defined above there is no halogen atom.
Therefore, at least there is one and R3, G3R3, R4, G4R4, R5 either corresponding X3, X4 or X5 group of G5R5 formulas Logical formula (I) compound（Wherein：G3, G4 with G5 as described above, and R3, R4 it is identical or different with R5, represent by one or The alkyl of multiple groups 1 of person or group 2 substituent groups substitution）Therefore it is respectively represented by one or more group 1 or group 2 at least one R3, R4 and R5 group of X3, X4 or X5 of the alkyl of substituent group substitution.
The specific aspect of the present invention is related to the compound of logical formula (I), and wherein A represents carbonyl (CO).
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein A represent oximido (C=N-O-H) or Oxime ether (C=N-O-R8), and R8 is represented by the aryl alkyl that either naphthenic base replaces or unsubstituted alkyl.Preferably, R8 Represent methyl.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein A represents CH2Group.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein A does not represent CH2Group.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein A representative-CR6R7 groups, R6 are represented Hydrogen atom, and R7 represents hydroxyl, alkyl either-OR8 groups R8 represents the alkyl that is replaced by aryl or naphthenic base or not Substituted alkyl.
Preferably, the present invention relates to the compounds of logical formula (I), wherein and A representative-CR6R7 groups, R6 represent hydrogen atom, and And R7 represents hydroxyl.
Another preferred aspect of the present invention is related to the compound of logical formula (I), wherein A representative-CR6R7 groups, R6 are represented Hydrogen atom, and R7 representative-OR8 groups, R8 are as defined above.Preferably, R8 representatives preferably comprise 1,2,3 or 4 carbon atom Alkyl.Even further preferably, R8 represent by aryl either cyclophane base substitution the alkyl aryl or naphthenic base particularly Including 6 carbon atoms.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein A representative-CR6R7 groups, R6 and R7 It is identical either different to represent hydroxyl, alkyl either-OR8 groups R8 represents the alkyl that is replaced by aryl or naphthenic base or not Substituted alkyl.
Another specific theme of the present invention is related to the compound of logical formula (I), wherein and X3 and X5 is identical or different, point R3 and R5 groups are not represented, and specifically, R3 and R5 represent hydrogen atom.
Another specific theme of the present invention is related to the compound of logical formula (I), wherein and X3 and X5 is identical or different, point R3 and R5 groups are not represented, and R3 and R5 is identical or different, represents by one or more 2 substitution of group 1 or group as defined above The alkyl or unsubstituted alkyl of base substitution.
Preferably, X3 and X5 is identical or different, respectively represents R3 and R5 groups, and R3 and R5 is identical or different, represents Preferably comprise the unsubstituted alkyl of 1,2,3 or 4 carbon atoms.Even further preferably, X3 and X5 is identical or different, first is represented Base.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein and X3 and X5 is identical or different, point Do not represent G3R3 either G5R5 groups G3 and G5 as described above, and R3 and R5 it is identical or different, represent hydrogen atom.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein and X3 and X5 is identical or different, point Do not represent G3R3 either G5R5 groups G3 and G5 as described above, and R3 and R5 it is identical either it is different represent it is by one or more A as defined above group 1 or group 2 substituent groups substitution alkyl or unsubstituted alkyl.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein and X3 and X5 is identical or different, point Do not represent G3R3 either G5R5 groups G3 and G5 as described above, and R3 and R5 it is identical either it is different represent it is by one or more A as defined above group 1 or group 2 substituent groups substitution alkyl.
Another specific aspect of the present invention is related to the compound of logical formula (I), and wherein X4 represents halogen atom（Bromine, chlorine, Fluorine, iodine）.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein and X4 represents R4 G4-R4 groups, G4 is as defined above, and R4 represents hydrogen atom.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein and X4 represents R4 G4-R4 groups, G4 is as defined above, and R4 is represented by one or more alkyl that group 1 or 2 substituent groups of group replace as defined above or do not taken The alkyl in generation.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein and X4 represents R4 G4-R4 groups, G4 is as defined above, and R4 is represented by one or more alkyl that group 1 or 2 substituent groups of group replace as defined above.Preferably, G4 represents oxygen atom and/or R4 represents the alkyl replaced by 1 substituent group of group, particularly-COOH.Even further preferably, X4 representatives- OC(CH3)2COOH、-OCH2COOH or-SC (CH3)2COOH group.
Another specific theme of the present invention is related to the compound of logical formula (I), wherein only one in described X3, X4 and X5 Represent R3, R4, R5, G3R3, G4R4 either G5R5 groups G3, G4 with G5 as described above, and R3, R4 it is identical with R5 or not Together, it represents by one or more alkyl that group 1 or 2 substituent groups of group replace as defined above.
Another specific theme of the present invention is related to the compound of logical formula (I), wherein only X4 generations in described X3, X4 and X5 Table R4 or G4R4, G4 is as defined above, and R4 is represented to be organized 1 as defined above by one or more or organize 2 substituent groups and be replaced Alkyl.
Another specific theme of the present invention is related to the compound of logical formula (I), wherein two in described X3, X4 and X5 Either Three Represents R3, R4, R5, G3R3, G4R4 or G5R5 groups, G3, G4 and G5 are as described above, and R3, R4 and R5 phase Same or different, representative is organized 1 by one or more or organizes the alkyl that 2 substituent groups replace as defined above.
Another specific aspect of the present invention is related to the compound of logical formula (I), wherein G3, G4 and/or G5 represent oxygen original Son.
Preferably, the present invention relates to the compounds of logical formula (I), wherein only one and G3R3 in described X3, X4 and X5, G4R4 G5R5 formulas correspond to, and G3, G4 and G5 represent oxygen atom, and either R5 is identical or different by R3, R4, represent by one Or multiple as defined above groups 1 or group 2 substituent groups substitution alkyl.
Even further preferably, the present invention relates to the compounds of logical formula (I), wherein in described X3, X4 and X5 only X4 groups with G4R4 formulas correspond to, and G4 represents hydrogen atom, and R4 is represented to be organized 1 as defined above by one or more or organize 2 substituent groups and be replaced Alkyl.
Another preferred aspect of the present invention is related to the compound of logical formula (I), wherein in described X3, X4 and X5 two or Person three is corresponding with G3R3, G4R4 or G5R5 formula, and G3, G4 and G5 represent oxygen atom, and R3, R4 and R5 represent by one or Person it is multiple as defined above group 1 or group 2 substituent groups substitution alkyl.
The specific aspect of the present invention is related to the compound of logical formula (I), wherein the substituent group is selected from 1 substituent group of group.It is excellent Selection of land, 1 substituent group of group are-COOR9 classes, and R9 is as defined above and preferably represents hydrogen atom either comprising 1,2,3,4,5 or 6 The alkyl of carbon atom.
The specific aspect of the present invention is related to the compound of logical formula (I), wherein only one and formula-OC in described X3, X4 and X5 (CH3)2COOR9 is corresponded to, and R9 is as defined above and preferably represents the alkane that hydrogen atom either includes 1,2,3,4,5 or 6 carbon atom Base.
Even more preferably, X4 representative-OC (CH3)2COOR9 groups, R9 is as defined above and preferably represents hydrogen atom or packet Alkyl containing 1,2,3,4,5 or 6 carbon atom.
The specific aspect of the present invention is related to the compound of logical formula (I), wherein X1 represents R1 G1R1 carbonyls, G1 As defined above, and R1 represents non-halogenated alkyl.
For example, X1 representatives-OCH2CH2CH3、-SCH2CH2CH3Group or there are the alkyl of 7 carbon atoms.
Preferably, R1 represents the non-halogenated alkyl for including 1,2 or 3 carbon atom.
Even more preferably, X1 representatives-CF3、-SCF3、-OCF3Group.
The specific aspect of the present invention is related to the compound of logical formula (I), wherein X1 represents hydrogen atom.Preferably, work as X1 When representing hydrogen atom, then X2 is different from hydrogen atom.
The specific aspect of the present invention is related to the compound of logical formula (I), wherein X2 represents hydrogen atom.Preferably, work as X2 When representing hydrogen atom, then X1 is different from hydrogen atom.
The specific aspect of the present invention is related to the compound of logical formula (I), wherein X2 represents halogen atom（Bromine, chlorine, fluorine, Iodine）.
The specific theme of the present invention is related to the compound of logical formula (I), wherein X2 represents R2 G2R2 groups, R2 and G2 As described above.Preferably, R2 represents hydrogen atom, CF3Group either includes the alkyl of 1,2,3,4,5,6,7 or 8 carbon atom. Even further preferably, X2 representative-OR groups, R represent alkyl ,-CF3、-OCF3、-OH。
The specific aspect of the present invention is related to the compound of logical formula (I), wherein D represents CH2Group.
Another specific theme of the present invention is related to the compound of logical formula (I), wherein G2 and D-shaped are at oxidation or vulcanization Heterocycle is to form the compound of following formula：
Preferably, G2 represents sulphur atom in logical formula (II).
Specific embodiment according to the present invention, preferred compound are as follows：
Compound 1：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
Compound 2：2- [2,6- dimethyl -4- [3- [2- (hexyloxy) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
Compound 3：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- benzyloxies propyl] phenoxy group] -2- first Base propionic acid
Compound 4：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] phenoxy group] -2- methyl Propionic acid
Compound 5：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- methoxy iminos propyl] phenoxy group] - 2 Methylpropionic acid
Compound 6：2- [2,6- dimethyl -4- [3- [4- (methoxyl group) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
Compound 7：2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxyacetic acid
Compound 8：2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
Compound 9：2- [2- methyl -4- [3- [4- (heptyl) phenyl] -3- oxopropyls] phenoxy group] -2 Methylpropionic acid
Compound 10：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- ethoxycarbonyl propyls] phenoxy group] -2- Methylpropanoic acid
Compound 11：2- [2,6- dimethyl -4- [3- [2- (trifluoromethyl) phenyl] -3- oxopropyls] phenoxy group] -2- Methylpropanoic acid
Compound 12：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] propyl] phenoxy group] -2 Methylpropionic acid
Compound 13：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2- first Base isopropyl propionate
Compound 14：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oximidos propyl] phenoxy group] -2- first Base propionic acid
Compound 15：2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- hydroxypropyls] phenoxy group] -2- first Base propionic acid
Compound 16：2- [2,6- dimethyl -4- [3- [2- (trifluoromethoxy) phenyl] -3- oxopropyls] phenoxy group] - 2 Methylpropionic acid
Compound 17：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- methoxy-propyls] phenoxy group] -2- Methylpropanoic acid
Compound 18：2- [2,6- dimethyl -4- [2,3- dihydro -4H-1- benzothiopyran derivative -4- ketone -2- bases] phenoxy group] -2- Methylpropanoic acid
Compound 19：2- [2- methyl -4- [3- [4- (rosickyite base) phenyl] -3- oxopropyls] phenoxy group] -2- methyl-props Acid
Compound 20：2- [3- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2 Methylpropionic acid
Compound 21：2- [4- [3- [4- (aminomethyl phenyl] -3- oxopropyls] phenoxy group] -2 Methylpropionic acid
Compound 22：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- cyclohexyl methoxies propyl] benzene oxygen Base] -2 Methylpropionic acid
Compound 23：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- butoxypropyls] phenoxy group] -2- Methylpropanoic acid
Compound 24：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- isopropoxide propyls] phenoxy group] - 2 Methylpropionic acid
Compound 25：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- cyclohexylethoxy radicals propyl] benzene oxygen Base] -2 Methylpropionic acid
Even further preferably, present invention is preferably related to following compounds：
Compound 1：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid；
Compound 2：2- [2,6- dimethyl -4- [3- [2- (hexyloxy) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid；
Compound 8：2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid；
Compound 13：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2- first Base isopropyl propionate；
Compound 16：2- [2,6- dimethyl -4- [3- [2- (trifluoromethoxy) phenyl] -3- oxopropyls] phenoxy group] - 2 Methylpropionic acid.
The compound of the present invention includes its pure stereoisomers（Diastereoisomer, enantiomter）Or mixing is three-dimensional Isomers, its racemic mixture, its geometric isomer, its tautomer, its salt, its hydrate, its solvate, it is solid Body form and their mixture.
The compound of the present invention can include one or several asymmetric centers.The present invention includes pure stereoisomer （Diastereoisomer, enantiomter）Or mix stereoisomer and racemic mixture and geometric isomer.When need Want enantiomer-pure（Or enrichment）Product when, either chiral intermediate or root can be passed through by purifying final product According to typical method known to persons of ordinary skill in the art（For example use reagent and chiral catalyst）Asymmetric syntheses is carried out to come It obtains.The present invention some compounds can with different stabilizations tautomeric form, and all these forms and Their mixture is included in the present invention.
The invention further relates to the salt of " pharmaceutically acceptable " of the compounds of this invention.In general, the term refer to derived from organic or Inorganic base or acid have mild toxicity or avirulent salt.These salt can be in the final purification step of the compound of the present invention Middle acquisition is obtained by the salt is included in previous purified compound.
Some compounds of the present invention and their salt may have the solid form of several stabilizations.The present invention includes the present invention The all solids form of compound, including amorphous, multiform, monocrystalline and polycrystalline form.
The compound of the present invention can in a free form or solvation（Such as with pharmaceutically acceptable solvent such as water （Hydrate）Or ethyl alcohol）Form exist.
It is also included in the present invention with the compound of the present invention of one or more kinds of isotope labellings：These compounds exist It is identical in structure, and the difference is that at least one of structure atom is by isotope（It is radioactive or on-radiation） Instead of.May include the example of the isotope in the structure of the compound of the present invention can be selected from hydrogen, carbon, oxygen and sulphur, such as Respectively2H、3H、13C、14C、 18O、17O、35S.Particularly preferred radioactive isotope, because they are in the internal life of the substance It is easy to prepare and detect in the research range of object availability.Particularly preferred heavy isotope（Such as2H）, because they grind in analysis It is used as internal standard in studying carefully.
The invention further relates to the methods that the compound of formula (I) is led in synthesis as defined above.
The method of the present invention includes：
In alkalinity or acid medium, the mixing of at least one formula (A) compound and at least one formula (B) compound The step of (i),
Wherein, X1, X2, X3, X4 and X5 have definitions given above,
Then, the reduction step (ii) of gained compound,
And last, the introducing step (iii) for making functional group connect.
The experiment condition of step (i) and step (ii) in acid or alkaline medium is for those skilled in the art For it is easy to implement and can vary widely.The step of synthesis, can be described under " embodiment " of the invention Those steps.
Preferably stoichiometrically method carries out for the mixing of two kinds of compounds.It is preferably in room temperature（About 18 DEG C -25 DEG C）With it is normal It is carried out under atmospheric pressure.
In alkaline medium, preferably react in highly basic such as alkali metal hydroxide（Such as sodium hydroxide）Or alkali metal alcohol Salt（Such as sodium ethoxide）In the presence of carry out.
In acid medium, preferably reacts and carry out in the presence of strong acids such as hydrochloric acid.
Gained compound can be detached by classical way known to persons of ordinary skill in the art.Then, they can To be used as such as drug or cosmetics.
Another theme of the present invention is related to the compound as described above as drug.
Another theme of the present invention is related to pharmaceutical composition, and the composition includes pharmaceutically in acceptable carrier At least one compound as described above, the compound may be with one or more kinds of other treatments and/or cosmetic activities Component combines.It is preferably used to and the relevant complication of metabolic syndrome, insulin resistance, diabetes, dyslipidemia, artery Atherosis, angiocardiopathy, obesity, hypertension, inflammatory disease（Asthma etc.）, neurodegenerative disease（Alzheimers Disease etc.）Or the pharmaceutical composition of the treatment of cancer.The pharmaceutical composition of the present invention is preferred for treating dyslipidemia.
It treats abnormal with lipid and/or carbohydate metabolism preferably through overall risk is reduced（Hyperlipidemia, II type glycosurias Disease, obesity etc.）The pharmaceutical composition of relevant cardiovascular risk factors.
Another theme of the present invention is related to including the alimentation composition of at least one compound as described above.
Another theme of the present invention is related at least one compound as described above and is used to prepare for treating a variety of diseases Disease, especially with the relevant disease of metabolic disorder（Such as dyslipidemia）Pharmaceutical composition purposes.More generally, of the invention Theme be related at least one above-mentioned compound be used to prepare for treat with lipid and/or the relevant painstaking effort of abnormal carbohydrate metabolism Pipe risk factors and thus to reduce the purposes of the pharmaceutical composition of overall risk.
Such as（But without limitation）, the compound of the present invention can advantageously with it is obtainable currently on the market or Other treatments of exploitation and/or applications of cosmetic agents administering drug combinations, such as：
Antidiabetic：Succagoga（Sulfonylurea（Glibenclamide, Glimepiride, gliclazide etc.）And meglitinide （glinides）（Repaglinide, Nateglinide etc.））, Alpha-glucosidase inhibitor, PPAR gamma agonists（Thiazolidinediones are such as Rosiglitazone, Pioglitazone）, mixing PPAR α/gamma agonist（For Sai Gelieta（tesaglitazar）, Mo Gelieta （muraglitazar））, full PPAR（The compound of three kinds of PPAR hypotypes is activated simultaneously）, biguanides（Melbine）, dipeptidyl peptidase Enzyme IV inhibitor（MK-431, vildagliptin（vildagliptin））, glucagon-like peptide -1（GLP-1）Agonist（Yi Zena Too）Deng.
Insulin
Lipid-loweringing and/or norcholesterol molecule：Fibrates（Fenofibrate, Gemfibrozil）, HMG CoA reductases or hydroxyl Ylmethyl glutaryl CoA reductase inhibitor（Statins, such as Atorvastatin, Simvastatin, Fluvastatin）, cholesterol Absorption inhibitor（Ezetimibe, phytosterol）, CETP or cholestery ester transfer protein inhibitors（Torcetrapib （torcetrapib））, ACAT or acyl-coenzyme a cholesterol acyltransferase inhibitor（Avasimibe, Yi Lumaibu （eflucimibe））、MTP（Microsomal triglyceride transfer protein）Inhibitor, bile acid multivalent chelator（Cholestyramine）, dimension Raw element E, polyunsaturated fatty acid, omega-fatty acid, nicotinic acid derivates（Niacin）Deng.
Rescinnamine and depressor：ACE（Angiotensin-Converting）Inhibitor（Captopril, enalapril, thunder Meter Pu Li or quinapril）, angiotensin-ii receptor inhibitor（Losartan, Valsartan, Telmisartan, angstrom slope sand are smooth （eposartan）, Irbesartan etc.）, Beta receptor blockers（Atenolol, metoprolol, labetalol, Propranolol）, thiazide and Non- thiazide diuretic（Frusemide, indapamide, hydrochlorothiazide, aldosterone antagonist class）, vasodilator, calcium channel blocking Agent（Nifedipine, felodipine, Amlodipine, diltiazem or Verapamil）Deng.
Anti-platelet agents：Aspirin, ticlopidine, Dipyridamole, clopidogrel, Flurbiprofen etc..
Slimming drugs：Sibutramine, lipase inhibitor（Orlistat）, PPAR δ, cannabinoid cb 1 receptor antagonist（Profit Mo Naban）Deng.
Anti-inflammatory agent：For example, cortex hormone of aadrenaline（Prednisone, betamethasone, dexamethasone, prednisolone, first sprinkle Buddhist nun Dragon, hydrocortisone etc.）, NSAID or the non-steroidal anti-inflammatory drugs derived from indoles（Indomethacin, sulindac）, aryl alkanoic acid （arylcarboxylic）Class NSAID（Non-steroidal anti-inflammatory drugs）（Tiaprofenic Acid, Diclofenac, Etodolac, Flurbiprofen, cloth Ibuprofen, Ketoprofen, naproxen, Nabumetone, alminoprofen）, NSAID derived from former times health（Non-steroidal anti-inflammatory drugs）（Meloxicam, Piroxicam, tenoxicam）, NSAID from that fragrant esters（Non-steroidal anti-inflammatory drugs）, COX2 selective depressants（Plug carrys out former times Cloth, rofecoxib）Deng.
Antioxidant：Such as probucol etc..
Medicament for treating cardiac insufficiency：Thiazide and non-thiazide diuretic（Frusemide, indapamide, hydrogen chlorine Thiazine, aldosterone antagonist class）, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe（Captopril, enalapril, Ramipril or quinapril）, digitalis drug （Digoxin, foxalin）, Beta receptor blockers（Atenolol, metoprolol, labetalol, Propranolol）, phosphodiesterase suppression Preparation（Enoximone, milrinone）Deng.
Medicament for treating coronary insufficiency：Beta receptor blockers（It is atenolol, metoprolol, labetalol, general Naphthalene Luo Er）, calcium channel blocker（Nifedipine, the felodipine either general place of Amlodipine, benzyl, diltiazem or Wella Pa rice）、NO（Nitric oxide）Donor（Trinitin, Isosorbide Nitrate, molsidomine）, amiodarone etc..
Anticarcinogen：Cytotoxic agent（With DNA（DNA）The drug of interaction, alkylating agent, cis-platinum and spread out Biology）, cytocide（GnRH（Gonadotropin-releasing hormone (GRH)）Analog, SMS 201-995, progesterone, antiestrogenic Medicine, aromatase inhibitor etc.）, immune response modifier（Interferons, IL2 etc.））Deng.
Antiasthmatic, such as bronchodilator（β 2 receptor agonist）, cortex hormone of aadrenaline, color thuja acid salt, leukotriene Receptor antagonist（Montelukast）Deng.
Cortex hormone of aadrenaline for treating skin disease such as psoriasis and dermatitis
Vasodilator and/or anti-ischemic（Fourth cough up place, ginkgo biloba p.e, naftidrofuryl, pentoxifylline, Piribedil）Deng.
The invention further relates to for treating the method with lipid and/or the relevant disease of glycometabolism, the method includes to A effective amount of compound as defined above or pharmaceutical composition is administered in individual, particularly people.Within the scope of the invention, term " effective quantity " refers to the chemical combination object amount for being enough to generate desired biology effect.Within the scope of the invention, term " individual " refers to the food in one's mouth Newborn animal and particularly refer to people.
Term " treatment " refers to curative, suiting the medicine to the illness or preventative treatment.Therefore, the compound of the present invention can be used In the individual with diagnosed disease（Such as mammal, the especially mankind）.The compound of the present invention can be used for delay or Person slows down the progress of the disease or prevents the further progress of disease, thus improves the illness of patient.Finally, of the invention Compound, which can deliver medicine to, may usually suffer from the disease or the healthy individuals with the material risk for suffering from the disease.
The pharmaceutical composition of the present invention advantageously comprise within the scope of one or more kinds of pharmacy acceptable excipient or Carrier（Such as the saline solution compatible and known to one of ordinary skill in the art with medicinal usage, physiological solution, etc. vadose solutions Liquid etc.）.The composition can include one or more kinds of reagents selected from dispersant, solubilizer, stabilizer, preservative etc. or Carrier.Reagent or carrier for these preparations（Liquid and/or injectable and/or solid）Specifically methylcellulose, Hydroxymethyl cellulose, carboxymethyl cellulose, Polysorbate 80, mannitol, gelatin, lactose, vegetable oil, Arabic gum, liposome Deng.The composition can be eventually by the galenica for ensuring extended release and/or sustained release（galenic forms）Or lid Human relations device（galenic devices）Mode be formulated into injectable suspensions, gel, oil, pill, suppository, powder, flexible glue The forms such as capsule, capsule, aerosol.For this kind of preparation, it can be advantageous to use the examination of such as cellulose, carbonate or starch Agent.
The compound of the present invention or composition can be administered with different forms in different ways.Thus, for example, it Can by systemic mode, oral, parenteral, by sucking or by inject for example by intravenously, muscle notes Penetrate, be subcutaneously injected, cutaneous routes, intra-arterial injection etc..For injection, the compound is usually can use such as syringe Or perfusion preserves come the form for the liquid suspension injected（conditioned）.
It should be understood that the speed and/or dosage about the injection can be by those skilled in the art according to trouble Person, pathology and administering mode etc. adjust.In general, the compound to be administered 1 μ g to 2g, preferably every time administration 0.1mg every time It is administered to 1g.If desired, can be with daily administration or even one day several times.Moreover, the composition of the present invention may include other medicines Agent or active constituent.
Description of the drawings
The abbreviation used in these attached drawings：
- Cpd=compound；
- Ctrl=control；
- mpk=mg/kg/ days；
- LDL- cholesterol=low density lipoprotein cholesterol；
- HDL- cholesterol=high-density lipoprotein cholesterol；
- VLDL- cholesterol=C-VLDL；
Fig. 1-1 to 1-66：According to the in-vitro evaluation of the PPAR activating properties of the compounds of this invention of the dosage
Use monkey kidney fibroblast（COS-7）, by measuring the transcriptional activity of chimera come in-vitro evaluation PPAR's Activation, the chimera by yeast Gal4 transcription factors DNA binding structural domains and different PPAR ligands binding structural domain Composition.
The compound is with 10-7Gal4-PPAR α, γ and δ chimeras are tested to 100 μM of dosage.Measure each Under the conditions of inducible factor, i.e., compound induction shine with compare induce it is the ratio between luminous.Inducible factor is higher, then institute Stating compound has more PPAR activating properties.
-Fig. 1-1,1-2,1-3：PPAR α of compound 1, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-4,1-5,1-6：PPAR α of compound 2, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-7,1-8,1-9：PPAR α of compound 3, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-10,1-11,1-12：PPAR α of compound 4, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-13,1-14,1-15：PPAR α of compound 5, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-16,1-17,1-18：PPAR α of compound 6, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-19,1-20,1-21：PPAR α of compound 7, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-2 2,1-23,1-24：PPAR α of compound 8, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-2 5,1-26,1-27：PPAR α of compound 9, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-2 8,1-29,1-30：PPAR α of compound 10, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-31,1-32,1-33：PPAR α of compound 11, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-34,1-35,1-36：PPAR α of compound 12, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-37,1-38,1-39：PPAR α of compound 14, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-40,1-41,1-42：PPAR α of compound 17, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-43,1-44,1-45：PPAR α of compound 18, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-46,1-47,1-48：PPAR α of compound 19, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-49,1-50,1-51：PPAR α of compound 20, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-52,1-53,1-54：PPAR α of compound 21, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-55,1-56,1-57：PPAR α of compound 22, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-58,1-59,1-60：PPAR α of compound 23, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-61,1-62,1-63：PPAR α of compound 24, the in-vitro evaluation of γ, δ activating property；
-Fig. 1-64,1-65,1-66：PPAR α of compound 25, the in-vitro evaluation of γ, δ activating property；
Fig. 2-1 to 2-9：The reducing blood lipid property and stimulation HDL- courages of the compounds of this invention carried out on ApoE2/E2 mouse The interior evaluating of the property of sterol synthesis
Evaluation the compound of the present invention is to passing through E2 hypotype apo Es in vivo（E2/E2）The shadow of the mouse of humanization It rings.
With the compound of the present invention oral medication 8 or after 14 days, the total cholesterol of the E2/E2 mouse of dyslipidemia is measured Ratio, triglycerides ratio and blood plasma free fatty acid ratio.By these parameters and derive from control-animal（The change of the unused present invention Close the animal of object treatment）Parameter make comparisons：The reducing blood lipid effect of the differential disply the compound of the present invention measured.
-Fig. 2-1：With compound 1 with the blood plasma cholesterol level after 50mpk drug treatments 8 days；
-Fig. 2-2：With compound 1 with the plasma triglyceride level after 50mpk drug treatments 8 days；
-Fig. 2-3：With compound 8 with the blood plasma cholesterol level after 3-10mpk drug treatments 14 days.
Also evaluated by measuring the expression of participation lipid and/or the gene of carbohydate metabolism and energy dissipation in hepatic tissue The effect of the compound of the present invention.Each horizontal expression about reference gene 36B4 of gene expression is subjected to standard Change.Then inducible factor is calculated, i.e.,（The compound of the present invention induction）Relative signal with and control group relevant relative value The ratio of average value.Inducible factor is higher, then the compound gets over the expression that highland promotes hepatic gene.Final result is expressed as The average value of induction value derived from each experimental group.
-Fig. 2-4：With compound 1 with 50mpk drug treatments 8 days after, PDK4 in the hepatic tissue of E2/E2 mouse（Pyruvic acid is de- Hydrogen kinase enzyme, hypotype 4）Expression
-Fig. 2-5：With compound 1 with 50mpk drug treatments 8 days after, ApoCIII in the hepatic tissue of E2/E2 mouse（Carry fat PROTEIN C 3）Expression
-Fig. 2-6：With compound 1 with 50mpk drug treatments 8 days after, ACO in the hepatic tissue of E2/E2 mouse（Acyl-CoA Oxidizing ferment 1, palmityl）Expression
-Fig. 2-7：With compound 8 with 3-10mpk drug treatments 14 days after, the expression of PDK4 in the hepatic tissue of E2/E2 mouse
-Fig. 2-8：With compound 8 with 3-10mpk drug treatments 14 days after, ApoCIII in the hepatic tissue of E2/E2 mouse Expression
-Fig. 2-9：With compound 8 with 3-10mpk drug treatments 14 days after, the expression of ACO in the hepatic tissue of E2/E2 mouse
Fig. 3-1 to 3-6：The reducing blood lipid property of the compounds of this invention carried out on db/db mouse and to HDL- cholesterol The interior evaluating of the stimulation property of synthesis
After the compound of the present invention oral medication 28 days, by measuring HDL cholesterol and triglycerides and plasma free The level of aliphatic acid carrys out influence of the interior evaluating the compound of the present invention to db/db mouse.These parameters with derive from control-animal （The animal of unused the compound of the present invention treatment）Parameter make comparisons：The drop blood of the differential disply the compound of the present invention measured Fat effect.
-Fig. 3-1：It is horizontal with the plasma HDL-cholesterol after 50mpk drug treatments 28 days with compound 8
-Fig. 3-2：With compound 8 with the plasma triglyceride level after 50mpk drug treatments 28 days；
-Fig. 3-3：With compound 8 with the plasma free fatty acid level after 50mpkg drug treatments 28 days.
Also by measuring hepatic tissue and muscle（Bone）The gene of lipid and/or glycometabolism and energy dissipation is participated in tissue Expression evaluate the effect of the compound of the present invention.By each level of gene expression about reference gene 36B4 in hepatic tissue In expression or be standardized about expressions of the reference gene 18S in gastrocnemius skeletal muscle.Then it calculates and lures Inducement, i.e.,（The compound of the present invention induction）Relative signal with and the relevant relative value of control group average value ratio.It lures Inducement is higher, then the compound gets over the expression that highland promotes gene.Final result is expressed as derived from each experimental group The average value of induction value.
-Fig. 3-4：With compound 8 with 50mpk drug treatments 28 days after, the expression of PDK4 in the hepatic tissue of db/db mouse
-Fig. 3-5：With compound 8 with 50mpk drug treatments 28 days after, ACO in the hepatic tissue of db/db mouse（Acyl-coenzyme A oxidizing ferment 1, palmityl）Expression
-Fig. 3-6：With compound 8 with 50mpk drug treatments 28 days after, the table of UCP2 in the skeletal muscle tissue of db/db mouse It reaches
Fig. 4-1：It is treated and is secreted with the MCP1 of the monocyte of PMA stimulations, body with the compound of the present invention by measurement The antiinflammatory property of outer evaluation the compound of the present invention
It is handled 24 hours by measurement the compound of the present invention and uses PMA simultaneously（Phorbol 12-myristinate 13- Acetic acid esters（Phorbol 12-myristate 13-acetate）, it promotes the inflammatory response of cell and them is promoted to be divided into Macrophage）The MCP1 of the THP1 monocytes of stimulation（Monocyte chemoattractant protein-1）Secretion, to evaluate the chemical combination of the present invention Object antiinflammatory efficacy.MCP-1 secretions are fewer, then the compound of the present invention more inhibits inflammatory reaction.
-Fig. 4-1：After being handled 24 hours with 1 μM of administration with compound 8, the MCP1 of THP1 monocytes secretes
Statistical analysis
Statistical research is examined by t（°/°°/°°°）And/or single argument ANOVA variance analyses and subsequent figure base (Tukey) it examines（*/**/***）Composition.According to the value of parameter p, compared with the control group by result：
°/*：p<0.05；°°/**：p<0.01；°°°/***：p<0.001.
Embodiment
Standard reagent and catalyst are commercially available（Aldrich, Alfa Aesar, Acros, Fluka or Lancaster）.
Proton NMR spectrum (NMR1H it) is measured on Bruker AC300P spectrometers.Chemical shift is with ppm （Parts per million）It indicates, the division of NMR signal is stated with common abbreviation.
Embodiment 1：Synthesize the general step of the compounds of this invention
The compound of the present invention uses the compound be claimed in United States Patent (USP) 2005176808 or described, by also One of former and subsequent step as described below and obtain.
General Background：Diphenylprop ketenes is restored with triethylsilane
Triethylsilane is added into the dichloromethane solution of diphenyl propylene -2- ketone, trifluoroacetic acid is then added dropwise（7.5 Equivalent）.Reaction mixture is stirred at room temperature, reaction tracking is carried out by thin-layered chromatography.Reaction mixture is washed with water.With Dichloromethane aqueous layer extracted.Combined organic layer magnesium sulfate is dry and is concentrated under reduced pressure.Residue carries out column chromatography（It prepares HPLC, cellular glass（Merck）RP18 12μm 100, column：25*250mm）.
General step B：Diphenylprop ketenes is restored with silicon tetrachloride
Sodium iodide is added into the acetonitrile solution of diphenyl propylene -2- ketone, silicon tetrachloride is then added dropwise.It is stirred at room temperature Reaction mixture carries out reaction tracking by thin-layered chromatography.After 30 minutes to 2 hours, by mixture between chloroform and water Distribution.With chloroform aqueous layer extracted.Combined organic layer is dried with sodium sulfite, then dry with magnesium sulfate and be concentrated under reduced pressure.It is surplus Excess carries out column chromatography（Prepare HPLC, cellular glass（Merck）RP18 12μm 100, column：25*250mm）.
General step C：The synthesis of oxime and oxime ether
O- alkyl hydroxylamine hydrochlorides are added into the pyridine solution of diphenylprop -3- ketone（O-alkylhydroxylamine hydrochloride）.After reflux 16 hours, mixture is concentrated under reduced pressure.Residue carries out column chromatography.
General step D：The synthesis of alcohol
Sodium borohydride is added into the ethanol solution of diphenylprop -3- ketone.By reaction mixture at 50 DEG C（122℉）Under stir It mixes 16 hours.After cooling, reaction mixture is made to hydrolyze and be concentrated under reduced pressure.By residue between dilute hydrochloric acid solution and dichloromethane Distribution.
Organic layer is washed with water, and magnesium sulfate is dry and is concentrated under reduced pressure.Residue carries out column chromatography（Prepare HPLC, porous Glass（Merck）RP18 12μm 100, column：25*250mm）.
General step E：The synthesis of ether
By solution of the diphenylprop -3- alcohol in water/alcohol mixture suitable in the presence of the trifluoroacetic acid of catalytic amount At a temperature of firmly stir, be then concentrated under reduced pressure.Residue is extracted with dichloromethane.Combined organic layer is dried with magnesium sulfate, Filtering, is then concentrated under reduced pressure.Residue carries out column chromatography（Prepare HPLC, cellular glass（Merck）RP18 12μm 100, Column：25*250mm）.
Embodiment 2：The synthesis of the compounds of this invention
Compound 1：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
According to the general Background, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxo propyl-s 2- are used Alkenyl] phenoxy group] -2 Methylpropionic acid and 1.3 equivalent triethylsilanes prepare the compound；
Appearance：White solid；F=109-110℃.
NMR 1H(300MHz,CDCl3,δ in ppm):1.42(s,6H),2.19(s,6H),2.53(s,3H),2.89 (t,2H,J=7.59Hz),3.25(t,2H,J=7.59Hz),6.89(s,2H),7.31(d,2H,J=8.17Hz),7.88(d,2H, J=8.17Hz)。
MS(ES-MS):385.3(M-1)。
Compound 2：2- [2,6- dimethyl -4- [3- [2- (hexyloxy) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
According to the general Background, 2- [2,6- dimethyl -4- [3- [2- (hexyloxy) phenyl] -3- oxo propyl-s 2- are used Alkenyl] phenoxy group] triethylsilane of -2 Methylpropionic acid and 1 equivalent prepares the compound；
Appearance：White solid；F=73-75℃.
NMR 1H(300MHz,CDCl3,δ in ppm):0.89(t,3H,J=6.72Hz),1.32(m,4H),1.45(m, 2H),1.52(s,6H),1.82(m,2H),2.21(s,6H),2.93(t,2H,J=8.19Hz),3.33(t,2H,J=8.19Hz), 4.05(t,2H,J=6.42Hz),6.87(s,2H),6.95(m,1H),7.01(m,1H),7.44(m,1H),7.68(dd,1H,J= 1.77Hz,J=7.89Hz)。
MS(ES-MS):439.4(M-1)。
Compound 3：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- benzyloxies propyl] phenoxy group] -2- first Base propionic acid
At 0 DEG C, in 15 minutes, to 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] benzene Oxygroup] -2 Methylpropionic acid N,N-dimethylformamide solution be added sodium hydride（2.2 equivalent）.Then benzyl bromide is added （benzyle bromide）（2.2 equivalent）, and mixture is stirred at room temperature 16 hours.By mixture in saturated ammonium chloride It is distributed between solution and ethyl acetate.Combined organic layer is dried with magnesium sulfate, then filtering is concentrated under reduced pressure.
In the presence of 2N sodium hydroxide solutions（20 equivalents）, residue is dissolved in ethyl alcohol.Reaction mixture stirring 6 is small When and be concentrated under reduced pressure.Residue is acidified with dilute hydrochloric acid solution, is then extracted with dichloromethane.Combined organic layer is dry with magnesium sulfate Dry, then filtering is concentrated under reduced pressure.Residue carries out column chromatography（Prepare HPLC, cellular glass（Merck）RP18 12μm 100, column：25*250mm）
Appearance：Pale solid；F=69-71℃.
NMR 1H(300MHz,CDCl3,δ in ppm):1.49(s,6H),1.90(m,1H),2.14(m,1H),2.19(s, 6H),2.52(m,1H),2.52(s,3H),2.68(m,1H),4.24(d,1H,J=11.8Hz),4.28(t,1H,J=5.25Hz), 4.47(d,1H,J=11.8Hz),6.77(s,2H),7.31(m,9H)。
MS(ES-MS):477.3(M-1)。
Compound 4：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] phenoxy group] -2- methyl Propionic acid
According to the general step D, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] are used Phenoxy group] sodium borohydrides of -2 Methylpropionic acid and 3 equivalents prepares the compound；
Appearance：Yellowish solid；F=49-51℃.
NMR 1H(300MHz,CDCl3,δ in ppm):1.52(s,6H),2.04(m,2H),2.22(s,6H),2.5(s, 3H),2.63(m,2H),4.66(dd,1H,J=5.7Hz,J=7.5Hz),6.84(s,2H),7.27(m,4H)。
MS(ES-MS):389.3(M+1)。
Compound 5：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- methoxy iminos propyl] phenoxy group] - 2 Methylpropionic acid
According to the general step C, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxos third are used Base] phenoxy group] -2 Methylpropionic acid prepares the compound；
Appearance：Yellowish viscous oil.
NMR 1H(300MHz,CDCl3,δ in ppm):1.50(s,6H),2.21(s,6H),2.49(s,3H),2.73(m, 2H),2.96(m,2H),3.99(s,3H),6.84(s,2H),7.20(d,2H,J=8.47Hz),7.51(d,2H,J=8.47Hz)。
MS(MALDI TOF):416.4(M+1)。
Compound 6：2- [2,6- dimethyl -4- [3- [4- (methoxyl group) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
According to the general procedure step B, 2- [2,6- dimethyl -4- [3- [4- (methoxyl group) phenyl] -3- oxos are used Propyl- 2- alkenyls] phenoxy group] -2 Methylpropionic acid, 5 equivalents sodium iodides and 5 equivalent silicon tetrachlorides prepare the compound；
Appearance：White solid；F=279-281℃.
NMR 1H(300MHz,CDCl3,δ ppm):1.52(s,6H),2.22(s,6H),2.94(t,2H,J=7.59Hz), 3.20(t,2H,J=7.59Hz),3.87(s,3H),6.88(s,2H),6.93(d,2H,J=8.76Hz),7.95(d,2H,J= 8.76Hz)。
MS(ES-MS):369.3(M-1)。
Compound 7：2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxyacetic acid
According to the general procedure step B, 2- [2,6- dimethyl -4- [3- [4- (methoxyl group) phenyl] -3- oxos are used Propyl- 2- alkenyls] phenoxyacetic acid, 5 equivalents sodium iodides and 5 equivalent silicon tetrachlorides prepare the compound；
Appearance：White solid；F=138-139℃.
NMR 1H(300MHz,CDCl3,δ ppm):2.28(s,6H),2.54(s,3H),2.96(t,2H,J=7.60Hz), 3.24(t,2H,J=7.60Hz),4.45(s,2H),6.92(s,2H),7.27(d,2H,J=8.47Hz),7.88(d,2H,J= 8.47Hz)。
MS(ES-MS):357.2(M-1)。
Compound 8：2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- oxopropyls] phenoxy group] -2- methyl Propionic acid
According to the general procedure step B, 2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- oxos are used Propyl- 2- alkenyls] phenoxy group] -2 Methylpropionic acid, 5 equivalents sodium iodides and 5 equivalent silicon tetrachlorides prepare the compound；
Appearance：White solid；F=89-92℃.
NMR 1H(300MHz,CDCl3,δ ppm):1.06(t,3H,J=7.30Hz),1.54(s,6H),1.85(m,2H), 2.23(s,6H),2.95(t,2H,J=7.75Hz),3.22(t,2H,J=7.75Hz),3.99(t,2H,J=6.57Hz),6.89 (s,2H),6.93(d,2H,J=8.91Hz),7.95(d,2H,J=8.91Hz)。
MS(ES-MS):397.3(M-1)。
Compound 9：2- [2- methyl -4- [3- [4- (heptyl) phenyl] -3- oxopropyls] phenoxy group] -2 Methylpropionic acid
According to the general procedure step B, 2- [2- methyl -4- [3- [4- (heptyl) phenyl] -3- oxo propyl- 2- alkene is used Base] phenoxy group] -2 Methylpropionic acid, 5 equivalents sodium iodides and 5 equivalent silicon tetrachlorides prepare the compound；
Appearance：White solid；F=53-54℃.
NMR 1H(300MHz,CDCl3,δ ppm):0.89(t,3H,J=6.72Hz),1.29(m,8H),1.61(s,6H), 1.62(m,2H),2.24(s,3H),2.66(t,2H,J=7.74Hz),2.99(t,2H,J=7.59Hz),3.26(t,2H,J= 7.59Hz),6.78(d,1H,J=8.46Hz),7.01(d,1H,J=8.46Hz),7.08(s,1H),7.26(d,2H,J= 8.16Hz),7.89(d,2H,J=8.16Hz)。
MS(ES-MS):423.3(M-1)。
Compound 10：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- ethoxycarbonyl propyls] phenoxy group] -2- Methylpropanoic acid
According to the general step E, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] are used Phenoxy group] -2 Methylpropionic acid is 2/3:It flows back in 1/3 ethanol/water mixture 72 hours and prepares the compound.
Appearance：Viscous oil.
NMR 1H(300MHz,CDCl3,δ in ppm):1.19(t,3H,J=7.02Hz),1.48(s,6H),1.87(m, 1H),2.07(m,1H),2.19(s,6H),2.5(s,3H),2.53(m,1H),2.64(m,1H),3.34(m,2H),4.14(dd, 1H,J=2.34Hz,J=5.55Hz),6.8(s,2H),7.24(m,4H)。
MS(ES-MS):417.4(M-1)。
Compound 11：2- [2,6- dimethyl -4- [3- [2- (trifluoromethyl) phenyl] -3- oxopropyls] phenoxy group] -2- Methylpropanoic acid
According to the general Background, 2- [2,6- dimethyl -4- [3- [2- (trifluoromethyl) phenyl] -3- oxo propyl-s are used 2- alkenyls] phenoxy group] triethylsilane of -2 Methylpropionic acid and 1 equivalent prepares the compound；
Appearance：Yellowish viscous oil.
NMR 1H(300MHz,CDCl3,δ ppm):1.53(s,6H),2.22(s,6H),2.95(t,2H,J=7.30Hz), 3.15(t,2H,J=7.30Hz),6.86(s,2H),7.32(m,1H),7.56(m,2H),7.71(m,1H)。
MS(ES-MS):407.3(M-1)。
Compound 12：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] propyl] phenoxy group] -2 Methylpropionic acid
To 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxo propyl- 2- alkenyls] phenoxy group] -2- methyl Triethylsilane is added dropwise in the trifluoroacetic acid solution of propionic acid（2.7 equivalent）.Reaction mixture is stirred 16 hours at room temperature.It is logical It crosses wave layer chromatography and carries out reaction tracking.Reaction mixture is washed with water.With dichloromethane aqueous layer extracted.Combined organic layer is used Magnesium sulfate is dried, and is then concentrated under reduced pressure.Residue carries out column chromatography（Eluant, eluent：Dichloromethane 95, methanol 5.）
Appearance：White solid；F=181-182℃.
NMR 1H(300MHz,DMSO-d6,δ ppm):1.24(s,6H),1.81(m,2H),2.16(s,6H),2.42(m, 2H),2.44(s,3H),2.54(m,2H),6.73(s,2H),7.15(m,4H)。
MS(ES-MS):371.4(M-1)。
Compound 13：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2- first Base isopropyl propionate
According to the general Background, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxo propyl-s 2- are used Alkenyl] phenoxy group] triethylsilane of -2 Methylpropionic acid isopropyl ester and 1 equivalent prepares the compound；
Appearance：White solid；F=64-65℃.
NMR 1H(300MHz,CDCl3,δ ppm):1.34(d,6H,J=6.5Hz),1.45(s,6H),2.19(s,6H), 2.54(s,3H),2.93(t,2H,J=7.89Hz),3.21(t,2H,J=7.89Hz),5.14(sep,1H,J=6.15Hz),6.84 (s,2H),7.26(d,2H,J=8.49Hz),7.89(d,2H,J=8.49Hz)。
MS(MALDI-TOF):429.3(M+1)。
Compound 14：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oximidos propyl] phenoxy group] -2- first Base propionic acid
According to the general step C, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] are used Phenoxy group] -2 Methylpropionic acid prepares the compound；
Appearance：White solid；F=144-147℃.
NMR 1H(300MHz,DMSO-d6,δ ppm):1.31(s,6H),2.11(s,6H),2.49(s,3H),2.61(dd, 2H,J=7,17Hz,J=8.76Hz),2.91(t,2H,J=8.47Hz),6.85(s,2H),7.23(d,2H,J=8.47Hz),7.54 (d,2H,J=8.47Hz),11.21(s,1H),12.81(s,1H)。
MS(ES-MS):400.3(M-1)。
Compound 15：2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- hydroxypropyls] phenoxy group] -2- first Base propionic acid
According to the general step D, 2- [2,6- dimethyl -4- [3- [4- (propoxyl group) phenyl] -3- oxopropyls] are used Phenoxy group] -2 Methylpropionic acid prepares the compound；
Appearance：Yellowish viscous oil.
NMR 1H(300MHz,CDCl3,δ ppm):1.05(t,3H,J=7.46Hz),1.50(s,6H),1.82(m,2H), 2.04(m,2H),2.20(s,6H),2.56(m,2H),3.93(t,2H,J=6.57Hz),4.63(t,1H,J=6.57Hz),6.81 (s,2H),6.88(d,2H,J=8.61Hz),7.25(d,2H,J=8.61Hz)。
MS(ES-MS):399.4(M-1)。
Compound 16：2- [2,6- dimethyl -4- [3- [2- (trifluoromethoxy) phenyl] -3- oxopropyls] phenoxy group] - 2 Methylpropionic acid
According to the general step B, 2- [2,6- dimethyl -4- [3- [2- (trifluoromethoxy) phenyl] -3- oxos are used Propyl- 2- alkenyls] phenoxy group] silicon tetrachloride of -2 Methylpropionic acid, the sodium iodide of 5 equivalents and 5 equivalents prepares the compound；
Appearance：Yellowish viscous oil.
NMR 1H(300MHz,CDCl3,δ ppm):1.53(s,6H),2.21(s,6H),2.94(t,2H,J=7.46Hz), 3.23(t,2H,J=7.46Hz),6.85(s,2H),7.36(m,2H),7.54(m,1H),7.63(dd,1H,J=1.74Hz,J= 7.59Hz)。
MS(ES-MS):423.0(M-1)。
Compound 17：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- methoxy-propyls] phenoxy group] -2- Methylpropanoic acid
According to the general step E, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] are used Phenoxy group] -2 Methylpropionic acid is 2/3:It flows back in 1/3 ethanol/water mixture 16 hours and prepares the compound；
Appearance：Viscous oil.
NMR 1H(300MHz,CDCl3,δ ppm):1.51(s,6H),1.89(m,1H),2.08(m,1H),2.21(s, 6H),2.5(s,3H),1.56(m,2H),3.22(s,3H),4.05(dd,1H,J=5.82Hz,J=7.32Hz),6.79(s,2H), 7.26(d,2H,J=8.46Hz),7.21(d,2H,J=8.46Hz)。
MS(ES-MS):401.3(M-1)。
Compound 18：2- [2,6- dimethyl -4- [2,3- dihydro -4H-1- benzothiopyran derivative -4- ketone -2- bases] phenoxy group] -2- Methylpropanoic acid
According to the general step B, 2- [2,6- dimethyl -4- [3- [2- (methyl mercapto) phenyl] -3- oxo propyl-s 2- are used Alkenyl] phenoxy group] silicon tetrachloride of -2 Methylpropionic acid, the sodium iodide of 6 equivalents and 6 equivalents prepares the compound；
Appearance：Yellowish solid；F=60-63℃.
NMR 1H(300MHz,CDCl3,δ ppm):1.53(s,6H),2.26(s,6H),3.18(dd,1H,J=3.35Hz,J =16.37Hz),3.28(dd,1H,J=12.87Hz,J=16.37Hz),4.62(dd,1H,J=3.35Hz,J=12.87Hz),7.06 (s,2H),7.22(d,1H,J=7.02Hz),7.29(m,1H),7.43 (m,1H),8.15(d,1H,J=7.89Hz)。
MS(ES-MS):369.1(M-1)。
Compound 19：2- [2- methyl -4- [3- [4- (rosickyite base) phenyl] -3- oxopropyls] phenoxy group] -2- methyl-props Acid
According to the general step B, 2- methyl -2- (2- methyl -4- (3- oxos -3- (4- (rosickyite base) phenyl) are used Propyl- 1- alkenyls) phenoxy group) silicon tetrachloride of propanoic acid tert-butyl ester, the sodium iodide of 3 equivalents and 3 equivalents prepares the compound；
Appearance：Viscous oil.
NMR 1H(300MHz,CDCl3,δ in ppm):1.07(t,3H,J=7.3Hz),1.61(s,6H),1.73(m, 2H),2.24(s,3H),2.98(m,4H),3.23(t,2H,J=7.32Hz),6.76(d,1H,J=8.19Hz),6.97(d,1H,J =8.19Hz),7.06(s,1H),7.29(d,2H,J=8.76Hz),7.86(d,2H,J=8.76Hz)。
MS(ES-MS):392.2(M-1)。
Compound 20：2- [3- [3- [4- (methyl mercapto) phenyl] -3- oxopropyls] phenoxy group] -2 Methylpropionic acid
According to the general step B, 2- [3- [3- [4- (methyl mercapto) phenyl] -3- oxo propyl- 2- alkenyls] benzene oxygen is used Base] silicon tetrachloride of -2 Methylpropionic acid, the sodium iodide of 7 equivalents and 7 equivalents prepares the compound；
Appearance：White solid；F=67-68℃.
NMR 1H(300MHz,CDCl3,δ ppm):1.62(s,6H),2.51(s,3H),3.01(t,2H, J=7.60Hz), 3.23(t,2H,J=7.60Hz),6.76(d,1H,J=8.16Hz),6.86(s,1H),6.93(d,1H,J=7.62Hz),7.16 (t,1H,J=7.89Hz),7.25(d,2H,J=8.48Hz),7.85(d,2H,J=8.48Hz)。
MS(ES-MS):357.3(M-1)。
Compound 21：2- [4- [3- [4- (aminomethyl phenyl] -3- oxopropyls] phenoxy group] -2 Methylpropionic acid
According to the general step B, 2- [4- [3- [4- (aminomethyl phenyl] -3- oxo propyl- 2- alkenyls] phenoxy group is used] - The silicon tetrachloride of 2 Methylpropionic acid, the sodium iodide of 5 amounts and 5 equivalents prepares the compound；
Appearance：White solid；F=124-125℃.
NMR 1H(300MHz,CDCl3,δ ppm):1.56(s,6H),2.43(s,3H),3.04(t,2H,J=7.52Hz), 3.27(t,2H,J=7.52Hz),6.9(d,2H,J=8.34Hz),7.19(d,2H,J=8.34Hz),7.24(d,2H,J= 8.19Hz),7.87(d,2H,J=8.19Hz)。
MS(ES-MS):325.3(M-1)。
Compound 23：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- butoxypropyls] phenoxy group] -2- Methylpropanoic acid
According to the general step E, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] are used Phenoxy group] -2 Methylpropionic acid carries out in 50/50 butanol/water at 70 DEG C 32 hours to prepare the compound；
Appearance：Viscous oil.
NMR 1H(300MHz,CDCl3,δ in ppm):0.81(t,3H,J=8.72Hz),1.38(m,2H),1.52(m, 2H),1.51(s,6H),1.86(m,1H),2.05(m,1H),2.21(s,6H),2.5(s,3H),2.55(m,1H),2.63(m, 1H),3.26(m,2H),4.13(m,1H),6.81(s,2H),7.24(m,4H)。
MS(ES-MS):443.5(M-1)。
Compound 24：2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- isopropoxide propyls] phenoxy group] - 2 Methylpropionic acid
According to the general step E, 2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- hydroxypropyls] are used Phenoxy group] -2 Methylpropionic acid carries out in 50/50 isopropanol/water at 70 DEG C 32 hours to prepare the compound；
Appearance：Viscous oil.
NMR 1H(300MHz,CDCl3,δ in ppm):1.09(d,3H,J=6.12Hz),1.14(d,3H,J=6.12Hz), 1.5(s,6H),1.79-1.90(m,1H),1.97-2.09(m,1H),2.2(s,6H),2.44-2.54(m,1H),2.5(s, 3H),2.67(m,1H),3.47(m,1H),4.27(dd,1H,J=5.27Hz,J=8.17Hz),6.82(s,2H),7.24(s, 4H)。
MS(ES-MS):429.3(M-1)。
According to one of described step A-E, to synthesize compound 22 about the method described in compound 1-21 and 23-24 and change Close object 25.
Embodiment 3：The in-vitro evaluation of the PPAR activating properties of the compounds of this invention
The PPAR activating properties of in-vitro evaluation the compounds of this invention.
Principle
Use monkey kidney fibroblast（COS-7）, by measuring the transcriptional activity of chimera come in-vitro evaluation PPAR's Activation, the chimera by yeast Gal4 transcription factors DNA binding structural domains and different PPAR ligands binding structural domain Composition.Compound is with 10-7- 100 μM of dosage is tested in Gal4-PPAR α, γ and δ chimeras.
Experimental program
Cell culture
COS-7 cells come from ATCC（American type culture collection）, cultivate in DMEM（Dulbecco improves her lattice That culture medium）In culture medium, 10% is supplemented in the culture medium（Volume/volume）Fetal calf serum, 100U/ml penicillin（Gibco, Paisley,UK）With 2mM L-Glutamines（Gibco,Paisley,UK）.Cell is at 37 DEG C in containing 5%CO2Moistening atmosphere Middle culture.
The description of plasmid for transfection
Plasmid Gal4 (RE) _ TkpGL3, pGal4-hPPAR α, pGal4-hPPAR γ, pGal4-hPPAR δ and pGal4- φ In document（Raspe E et al., 1999）In be described.By in pGal4- φ carriers clone by PCR amplification and with Corresponding DNA fragmentation acquisition structure pGal4-hPPAR α of the DEF structural domains of people PPAR α, PPAR γ and PPAR delta cell nuclear receptors, PGal4-hPPAR γ and pGal4-hPPAR δ.
Transfection
In the presence of 10% fetal calf serum, with 1/10 pGal4-PPAR/Gal4 (RE) _ TkpGL3 ratios, with 150ng's DNA hole-specifically COS-7 cells in Transfection ofsuspension liquid.These cells are coated in 96 orifice plates（4×104Cells/well）, then exist 37 DEG C are incubated 24 hours.Continue 24 hours into line activating in 37 DEG C, in the culture medium without serum with test compound.Experiment At the end of, make cell dissolution, and use Steady-LiteTMHTSPerkin Elmer) or Steady Glow Luciferase (Promega) measures the activity of luciferase according to the suggestion of supplier.
As a result
The compounds of this invention is tested in three kinds of PPAR hypotypes.Derived from compound 1-12,14, the result of 16-25 it is detailed It is expressed in figure（1-1）Extremely（1-66）In.
Inventors demonstrated that fluorescein in the cell handled with plasmid pGal4-hPPAR transfections and with the compounds of this invention The significant and dose-dependent raising of enzymatic activity.
Conclusion
Unexpectedly, experimental data shown in shows that the compound of the present invention is combined with PPAR and induced sharp in vitro Transcriptional activity living.
Embodiment 4：The reducing blood lipid property and stimulation HDL- courages of the compounds of this invention carried out on ApoE2/E2 mouse are solid The interior evaluating of the property of alcohol synthesis
Principle
After the E2/E2 mouse for treating dyslipidemia with the compound of the present invention, by measuring blood plasma lipide and analyzing liver The expression of middle PPAR target genes gene carrys out interior evaluating the compound of the present invention reducing blood lipid property.
Mouse model used is ApoE2/E2 mouse, is the transgenic mice with human apolipoprotein E hypotypes E2 （Sullivan PM et al., 1998）.In the mankind, this apolipoprotein is low-density and very low density lipoprotein（LDL-VLDL） A kind of component, it exists with tri- kinds of hypotypes of E2, E3 and E4.There is the mutation for influencing the 158th amino acids, the mutation in E2 hypotypes Considerably reduce the compatibility of the albumen and ldl receptor.Therefore, VLDL removings be there's almost no.Then, low-density occurs The combined hyperlipidemia of type III is accumulated and be referred to as to lipoprotein（High cholesterol and triglycerides ratio）.
PPAR α adjust the gene for participating in lipid transport（Apolipoprotein, such as Apo AI, Apo AII and Apo CIII；Film Transporter, such as FAT）With the gene of lipid catabolism（ACO, CPT-I or CPT-II, aliphatic acid tryptophan side-chain alpha）Table It reaches.Therefore, in the mankind and rodent, caused to recycle triglyceride levels reduction with the treatment of PPAR alpha activators.With the present invention Compound treatment after, measure blood plasma lipide ratio can evaluate the compounds of this invention PPAR agonist characteristics and reducing blood lipid effect Power.
In the mankind and rodent, the raising of plasma HDL-cholesterol ratio is sometimes resulted in PPAR activators for treating. Measure the ability that HDL- cholesterol can show the compound of the present invention stimulation HDL- cholesterol biosynthesis.
The PPAR alfa agonists property measured in vitro above can lead to target in liver, directly under the control of PPAR α The overexpression of gene：The gene that we have studied in this experiment is PDK-4（Participate in the enzyme of glycometabolism）、Apo CIII（Ginseng With the apolipoprotein of lipid-metabolism）And Acoxl（In mouse, Acoxl corresponds to the ACO genes of the mankind（Acyl-CoA oxidase, To the enzyme of free fatty beta oxidation mechanism key））.Therefore, after being treated with the compound of the present invention, PPAR α target bases are measured The transcriptional activity of cause can evaluate the reducing blood lipid property of the compounds of this invention.
Experimental program
The treatment of animal
Under 20 ± 3 DEG C of steady temperature, ApoE2/E2 transgenic mices are maintained at 12 hours/12 hours light/dark In cycle.After one week laundering period, mouse is weighed and is grouped, per 6 animals of group selection, so that they are measured before testing Weight and blood plasma lipide ratio be evenly distributed.Test compound is suspended in carboxymethyl cellulose（Sigma C4888）In, with Selected dosage is administered by tube feed in stomach, once a day, continues 8 days（Compound 1）, or once a day, continue 14 days（Chemical combination Object 8）.Animal can ad lib and drinking-water（Standard diet）.In the entire experiment process, the intake and weight for recording food increase Add.At the end of experiment, after fasting in 4 hours, by Animal Anesthesia, blood sample is acquired with (EDTA) anticoagulant, it then will be small Mouse weighs and makes its euthanasia.By with 3000 revs/min of centrifugations, 20 minutes separated plasmas.By Sample storage at+4 DEG C.
Liver specimens are acquired, is freezed in liquid nitrogen, is then stored in -80 DEG C for subsequent analysis.
The measurement of blood plasma lipide
Pass through enzyme dosage（bioMérieux-Lyon-France）, according to the suggestion of supplier, measure blood plasma lipide concentration （Total cholesterol and triglycerides）.
With the compounds of this invention oral medication 8 or after 14 days, plasma cholesterol ratio and triglycerides ratio are measured.It will These ratios with derive from control-animal（Unused the compound of the present invention treatment）Ratio make comparisons.Differential disply this hair measured The reducing blood lipid effect of bright compound.
Pass through quantitative RT PCR analysis gene expression
By using96 RNA kits（Macherey Nagel,Hoerdt,France）, according to The operation instruction of manufacturer extracts total serum IgE from liver fragment.
Then, by containing 1X buffer solutions in 20 μ l at 37 DEG C（Sigma）、1.5mM DTT、0.18mM dNTP （Promega）、200ng pdN6（Amersham）, 30U RNase inhibitors（Sigma）With 1 μ l MMLV-RT（Sigma）It is total It is reacted 1 hour in volume, by 1 μ g total serum IgEs（By using Ribogreen RNA quantification kits（Molecular Probes） It is quantitative）Reverse transcription is complementary DNA.
According to the suggestion of manufacturer, under 55 DEG C of hybridization temperature, in 96 orifice plates in the diluted reverse transcription solution of 5 μ l In, use MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la- Coquette, France) and iQ SYBR Green Supermix kits progress PCR quantitative experiments.It has used and has been studied The following specific primer pair of gene：
·PDK4：Synonymous primer：5’-TACTCCACTGCTCCAACACCTG-3’(SEQ ID NO：And antisense primer 1) 5’-GTTCTTCGGTTCCCTGCTTG-3’(SEQ ID NO:2))
·ApoCIII：Synonymous primer：5’-CTCTTGGCTCTCCTGGCATC-3’(SEQ ID NO：And antisense primer 3) 5’-GCATCCTGGACCGTCTTGGA-3’(SEQ ID NO:4)。
·ACO：Synonymous primer：5’-GAAGCCAGCGTTACGAGGTG-3’(SEQ ID NO：And antisense primer 5)：5’- TGGAGTTCTTGGGACGGGTG-3’(SEQ ID NO：6)
The amount for emitting fluorescence is directly proportional to the amount of cDNA that is existing and being expanded during PCR when reaction beginning.For The each target studied is tested by the system with serial dilution degree of several microlitres of different reverse transcription solution composition mixtures Row solution.As a result, the relative expression of each target is determined by using derived from the efficiency curve with the relevant point of PCR solution series It is horizontal.
Then, by the expression reference gene 36B4 of interested gene, (its specific primer is：Synonymous primer：5’- CATGCTCAACATCTCCCCCTTCTCC-3’(SEQ ID NO：And antisense primer 9)：5’- GGGAAGGTGTAATCCGTCTCCACAG-3’(SEQ ID NO：One of) 10) it is standardized.
Then, the inducible factor of each sample is calculated, i.e.,（The compound of the present invention induction）Relative signal with derived from pair According to the ratio of the average value of the relative value of group.Inducible factor is higher, then the compound gets over the expression that highland promotes gene.Finally As a result it is expressed as the average value of the induction value derived from each experimental group.
As a result
The measurement of blood plasma lipide
Fig. 2-1 is compared with compound 1 with total plasma cholesterol ratio after 50mpk drug treatments 8 days and dynamic derived from control The ratio of object.Unexpectedly, by treatment, cycle total cholesterol ratio very significantly reduces.
Fig. 2-2 is compared with compound 1 with plasma triglyceride ratio after 50mpk drug treatments 8 days and dynamic derived from control The ratio of object.Unexpectedly, by treatment, cycle triglycerides ratio very significantly reduces.
Fig. 2-3 compare with compound 8 with total plasma cholesterol ratio after 3 and 10mpk drug treatments 14 days and derived from pair According to the ratio of animal.Unexpectedly, by treatment, cycle total cholesterol ratio very significantly reduces.
Pass through quantitative RT PCR analysis gene expression
Inventors have also demonstrated that the compound of the present invention is the internal conditioning agent of PPAR expression of target gene.Fig. 2-4,2-5 and The results show that the liver table of the gene of 8 days induction coding PDK4 is administered with 50mpk to E2/E2 mouse for compound 1 shown in 2-6 What is reached dramatically increases（Fig. 2-4）, the reduction of the liver expression of the gene of induction coding ApoCIII（Fig. 2-5）, and induce coding The liver expression of the gene of ACO dramatically increases（Fig. 2-6）.
The results show that induction in 14 days is administered to E2/E2 mouse with 3 and 10mpk in compound 8 shown in Fig. 2-7,2-8 and 2-9 Encode dramatically increasing for the liver expression of the gene of PDK4（Fig. 2-7）, induce subtracting for the liver expression of the gene of coding ApoCIII It is few（Fig. 2-8）, and the liver expression of the gene of coding ACO is induced to dramatically increase（Fig. 2-9）.
Particularly all genes of the enzyme of participation lipid and glycometabolism and their expression are encoded by chemical combination of the present invention The fact that object is adjusted strengthens the viewpoint for the great potential that these compounds are shown for treating metabolic disease.
Conclusion
Unexpectedly, experimental data shown in shows that the compound of the present invention induces reducing blood lipid effect in vivo（It reduces The blood plasma level of total cholesterol and triglycerides）.Experimental data shown in moreover, shows, the compound of the present invention adjust by The expression of the gene of the adjusting of the activation of PPAR, these gene codes particularly participate in the enzyme of lipid and glycometabolism.
Embodiment 5：The reducing blood lipid property of the compounds of this invention carried out on db/db mouse and to HDL- cholesterol biosynthesis Stimulation property interior evaluating
Principle
After being administered by oral route the db/db mouse for the treatment of dyslipidemia with the compound of the present invention, by measuring blood It starches the blood plasma level of lipid and the gene expression for analyzing PPAR target genes carrys out the reducing blood lipid of interior evaluating the compound of the present invention Matter.
Experimental program
The treatment of animal
Under 20 ± 3 DEG C of steady temperature, male db/db mouse are maintained to 12 hours/12 hours light/dark cycles In.After one week laundering period, mouse is weighed and is grouped, per 8 animals of group selection, makes the weight measured before experiment and blood The distribution for starching drugrlipid ratio is uniform.Test compound is suspended in carboxymethyl cellulose（Sigma C4888）In, with selected Dosage by intragastric gavage to animal be administered, once a day, continue 28 days.Animal can ad lib and drinking-water（Standard is drunk Food）.In the entire experiment process, the intake and weight gain of food are recorded.It at the end of experiment, will after fasting in 4 hours Animal Anesthesia acquires blood sample with anticoagulant (EDTA).Then mouse is weighed and makes its euthanasia.By with 3000 revs/min Centrifuge 20 minutes separated plasmas.By Sample storage at+4 DEG C.
Hepatic tissue and skeletal muscle sample are acquired, and is freezed in liquid nitrogen immediately, is then stored in -80 DEG C for subsequently dividing Analysis.
The measurement of blood plasma lipide
Pass through enzymatic assays（bioMérieux-Lyon-Franc）, according to the suggestion of supplier, measure plasma triglyceride Concentration.
The measurement of HDL- cholesterol
By phosphotungstate by low-density lipoprotein（VLDL and LDL）Precipitation.Sediment is removed by centrifugation.Pass through enzyme process It measures（bioMérieux-Lyon-Franc）, according to the suggestion of supplier, measure the HDL cholesterol being present in supernatant.
Pass through quantitative RT PCR analysis gene expression
Hepatic tissue
By using96 RNA kits（Macherey Nagel,Hoerdt,France）, according to The operation instruction of manufacturer extracts total serum IgE from liver fragment.
Skeletal muscle tissue
By using RNeasyFibrous Tissue kits（Qiagen）, according to the operation instruction of manufacturer, from Total serum IgE is extracted in gastrocnemius skeletal muscle fragment.
Then, by containing 1X buffer solutions in 20 μ l at 37 DEG C（Sigma）、1.5mM DTT、0.18mM dNTP （Promega）、200ng pdN6（Amersham）, 30U RNase inhibitors（Sigma）With 1 μ l MMLV-RT（Sigma）It is total It is reacted 1 hour in volume, by 1 μ g total serum IgEs（With spectrophotometric standard measure）Reverse transcription is complementary DNA.
According to the suggestion of supplier, under 55 DEG C of hybridization temperature, with the diluted reverse transcription solution of 5 μ l in 96 orifice plates, Use MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la- Coquette, France) and iQ SYBR Green Supermix kits progress PCR quantitative experiments.It has used and has been studied The following specific primer pair of gene：
·PDK4：Synonymous primer：5’-TACTCCACTGCTCCAACACCTG-3’(SEQ ID NO：And antisense primer 1) 5’-GTTCTTCGGTTCCCTGCTTG-3’(SEQ ID NO：2))
·ACO：Synonymous primer：5’-GAAGCCAGCGTTACGAGGTG-3’(SEQ ID NO：And antisense primer 5 ' -5) TGGAGTTCTTGGGACGGGTG-3’(SEQ ID NO：6)
·UCP2：Synonymous primer：5’-GTCGGAGATACCAGAGCACTGTCG-3’(SEQ ID NO：And reverse primer 7) 5’-CACATCAACAGGGGAGGCGA-3’(SEQ ID NO：8)
The amount for emitting fluorescence is directly proportional to the amount of cDNA that is existing and being expanded during PCR when reaction beginning.For The each target studied has been carried out by the system with serial dilution degree of several microlitres of different reverse transcription solution composition mixtures Row solution.As a result, the relative expression of each target is determined by using derived from the efficiency curve with the relevant point of PCR solution series It is horizontal.
Then, the expression by interested gene in hepatic tissue is about reference gene 36B4 (its specific primer For：Synonymous primer：5’-CATGCTCAACATCTCCCCCTTCTCC-3’(SEQ ID NO：And antisense primer 9)：5’- GGGAAGGTGTAATCCGTCTCCACAG-3’(SEQ ID NO：10) expression) is standardized, and will be interested About reference gene 18S, (its specific primer is expression of the gene in skeletal muscle tissue：Synonymous primer：5’- CGGACACGGACAGGATTGACAG-3'(SEQ ID NO：And antisense primer 11)：5’-AATCTCGGGTGGCTGAACGC-3' (SEQ ID NO：12) expression) is standardized.Then, the relevant inducible factor of each sample is calculated.Inducible factor Higher, then the compound gets over highland promotion gene expression.Final result is expressed as being averaged for the induction value of each experimental group Value.
As a result
The measurement of blood plasma lipide
Fig. 3-1 compare with compound 8 with after 50mpk drug treatments 28 days plasma HDL-cholesterol ratio and derived from pair According to the ratio of animal.Unexpectedly, HDL- cholesterol ratios obviously increase.
Fig. 3-2 and 3-3 compares the plasma triglyceride ratio after being treated 28 days with 50mpk with compound 8 and free fat Fat acid ratio and ratio derived from control-animal.Unexpectedly, by treatment, triglycerides ratio and free fatty are recycled Ratio is very significantly reduced.
Pass through quantitative RT PCR analysis gene expression
Inventors have also demonstrated that the compound of the present invention is the conditioning agent of PPAR expression of target gene.Fig. 3-4,3-5 and 3-6 Shown in the results show that compound 8 with 50mpk to db/db mouse be administered 28 days induction coding PDK4 and ACO gene liver Dirty expression dramatically increases（It is followed successively by Fig. 3-4, Fig. 3-5）, and induce the increasing of expression of the gene of coding UCP2 in skeletal muscle Add（Fig. 3-6）.Coding particularly participates in all genes and their expression of lipid and glycometabolism and the enzyme of energy dissipation The fact that adjusted by the compounds of this invention reinforces the compound of the present invention with the great potential for treating metabolic disease Viewpoint.
Conclusion
Unexpectedly, experimental data shown in shows, the compound of the present invention stimulate HDL cholesterol biosynthesis in vivo and And there is reducing blood lipid matter effect（The reduction of triglycerides and free fatty blood plasma level）.Moreover, disclosed experiment number According to display, the compound of the present invention adjusts expressing for the gene of the adjusting of the activation by PPAR, these gene codes are particularly joined With lipid and glycometabolism and the enzyme of energy dissipation.
Embodiment 6：The in-vitro evaluation of the antiinflammatory property of the compounds of this invention
Principle
It is handled 24 hours by measurement the compound of the present invention and uses PMA simultaneously（Phorbol 12-myristinate 13- Acetic acid esters, it promotes the inflammatory response of cell and them is promoted to be divided into macrophage）The MCP1 of the monocyte of stimulation（Monokaryon Cell chemotaxis albumen -1）Secretion, to evaluate the antiinflammatory efficacy of the compound of the present invention.MCP-1 secretions are fewer, then change of the invention It closes object and more inhibits inflammatory reaction.
Experimental program
The culture and processing of THP-1 cells
By THP-1 human monocyte cell lines（The sources ATCC）Culture is with 25mM hydroxyethyl piperazineethanesulfonic acids（Gibco； 42401-018）, 1% glutamine（Gibco；25030-24）, 1% penicillin/streptomycin（Biochrom AG；A2213）With 10% Decomplementation（decomplemented）Fetal calf serum（SVF.Gibco；In RPMI1640 culture mediums 26050-088).
Cell is coated on 24 orifice plates with the density of 870000 cells/wells（Primaria BD Falcon）In, then In 37 DEG C and 5%CO2Under in the culture medium containing 0.2% fetal calf serum, in 5ng/ml phorbol 12s-myristinate 13- second Acid esters（PMA）It is cultivated 24 hours in the presence of 1 μM of the compounds of this invention 8.The compound of the present invention is dissolved in dimethyl Asia Sulfone（DMSO,Fluka；41640）In.The effect of the compound of the present invention and the effect of individual DMSO are compared.
The measurement of MCP1 secretions
Processing culture medium is restored, ELISA kit is used《Human MCP-1 ELISA Set》（BD OptEIA； 555179）, according to the suggestion of manufacturer, measure MCP1 concentration.
MCP1 is placed on tablet, is identified by anti-MCP1 specific antibodies.The specific antibody itself is previously used oxidation The secondary antibody of object enzyme coupling specifically identifies.The dyeing generated by enzymatic activity is proportional with the amount of fixed MCP1, and It can be measured by spectrophotometry.A series of measurement are carried out from the point for representing known concentration, and thus calculate each sample MCP1 concentration.
Then inducible factor, the i.e. ratio of the signal of the compound of the present invention induction and the signal by control group induction are calculated Rate.The factor is smaller, then the compound more inhibits the secretion of MCP1.Final result is expressed as luring derived from each experimental group Lead the average value of value.
As a result
Present inventor have demonstrated that the compound of the present invention has antiinflammatory efficacy to external monocyte.It is tied shown in Fig. 4-1 Fruit shows that the MCP1 of 1 μM of 8 induced monocyte of the compounds of this invention secretion is substantially reduced.
Conclusion
Unexpectedly, disclosed experimental data is shown, the compound of the present invention has the monocyte stimulated by PMA There is antiinflammatory efficacy.
It summarizes
Present inventor have demonstrated that the compound of the present invention has reducing blood lipid property, lead to plasma cholesterol ratio and glycerine The reduction of three ester ratios also stimulates the synthesis of HDL- cholesterol.Moreover, present inventor have demonstrated that, the compound of the present invention can be adjusted Section coding particularly participates in the expression of lipid and the gene of glycometabolism and the enzyme of energy dissipation.
Inventors have also demonstrated that the compound of the present invention has antiinflammatory property.
These derive from internal and external the results show that the compound of the present invention is to such as dyslipidemia, type-2 diabetes mellitus With the treatment potentiality of the important diseases of obesity.
Bibliography
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Claims (15)

1. the compound and its salt of 1, the 3- diphenyl propanes derived from substitution, the compound has following general formula (I)：
Wherein：
X1 represents R1 G1-R1 groups；
X2 represents R2 G2-R2 groups；
X3 represents R3 G3-R3 groups；
X4 represents halogen atom, R4 G4-R4 groups；
X5 represents R5 G5-R5 groups；
R1 represents hydrogen atom or non-halogenated alkyl；
R2 represents hydrogen atom or non-halogenated alkyl；
R3, R4 the identical either different alkyl represented by one or more group 1 or group 2 substituent groups substitution or non-take with R5 Substituted alkyl；
G1, G2, G3, G4 are identical with G5 either different to represent oxygen atom or sulphur atom；
Wherein at least one of R3, R4 and R5 group represent the alkyl by one or more group 1 or group 2 substituent groups substitution；
A is represented：
(i) CR6R7 groups, wherein：
R6 represents hydrogen atom, and R7 representative-OR8 groups, R8 are defined as follows,
(ii) oximido C=N-O-H or oxime ether C=N-O-R8,
The identical either different alkyl or non substituted alkyl represented by aryl or naphthenic base substitution of R8；
D is represented：
(i) carbon atom (CH being connect with two hydrogen atoms2),
(ii) it is connect with both hydrogen atom and G2 to form oxidation or vulcanize the carbon atom of heterocycle；
1 substituent group of group is selected from-COOR9 and-CONR9R10；
2 substituent groups of group are selected from-SO3H and-SO2NR9R10；
R9 and R10 is identical either different to represent hydrogen atom or non substituted alkyl.
2. the compound of claim 1, which is characterized in that X4 represents R4 or G4-R4 groups,
G4 is as defined in claim 1, and
R4 represents the alkyl by one or more group 1 or group 2 substituent groups substitution.
3. the compound of claim 1, which is characterized in that G3, G4 and/or G5 represent oxygen atom.
4. the compound of claim 1, which is characterized in that the substituent group is selected from 1 substitution of group as defined in claim 1 Base.
5. the compound of claim 1, which is characterized in that X4 and formula-OC (CH3)2COOR9 is corresponded to, institute in R9 such as claim 1 Definition.
6. the compound of claim 1, which is characterized in that X3 and X5 is identical or different, respectively represents R3 and R5 groups, R3 and R5 represents alkyl or the non-substituted alkane for organizing 1 or group 2 substituent groups substitution as defined in claim 1 by one or more Base.
7. the compound of claim 1, which is characterized in that X1 represents R1 G1-R1 groups, determines in G1 such as claim 1 Justice, and R1 represents non-halogenated alkyl.
8. the compound of claim 1, which is characterized in that X2 represents hydrogen atom.
9. the compound of claim 1, which is characterized in that D representatives-CH2Group.
10. the compound of claim 1, which is characterized in that they are selected from：
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- methoxy iminos propyl] phenoxy group] -2 Methylpropionic acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- oximidos propyl] phenoxy group] -2 Methylpropionic acid；
2- [2,6- dimethyl -4- [2,3- dihydro -4H-1- benzothiopyran derivative -4- ketone -2- bases] phenoxy group] -2 Methylpropionic acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- cyclohexyl methoxies propyl] phenoxy group] -2- methyl-props Acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- butoxypropyls] phenoxy group] -2 Methylpropionic acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- isopropoxide propyls] phenoxy group] -2 Methylpropionic acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- cyclohexylethoxy radicals propyl] phenoxy group] -2- methyl-props Acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- benzyloxies propyl] phenoxy group] -2 Methylpropionic acid；
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- ethoxycarbonyl propyls] phenoxy group] -2 Methylpropionic acid；With
2- [2,6- dimethyl -4- [3- [4- (methyl mercapto) phenyl] -3- methoxy-propyls] phenoxy group] -2 Methylpropionic acid.
11. pharmaceutical composition, the composition is included at least one of pharmaceutically acceptable carrier such as claim 1- Compound defined in any one of 10, the compound optionally with one or more kinds of other treatments and/or cosmetic activity Agent combines.
12. pharmaceutical composition, the composition is included at least one of pharmaceutically acceptable carrier such as claim 1- Compound defined in any one of 10, the compound are combined with one or more kinds of following other compounds：
Antidiabetic
Insulin
Lipid-loweringing and/or norcholesterol molecule
Rescinnamine or depressor
Anti-platelet agents
Slimming drugs
Anti-inflammatory agent
Antioxidant
Medicament for treating cardiac insufficiency
Medicament for treating coronary insufficiency
Anticarcinogen
Antiasthmatic
For treating dermopathic cortex hormone of aadrenaline
Vasodilator
And/or anti-ischemic.
13. the pharmaceutical composition of claim 11 or 12 is being prepared for treating and the relevant complication of metabolic syndrome, pancreas islet Plain resistance, diabetes, angiocardiopathy, obesity, inflammatory disease, neurodegenerative disease or cancer drug in purposes.
14. the pharmaceutical composition of claim 11 or 12 is being prepared for treating dyslipidemia, atherosclerosis or hypertension Drug in purposes.
15. the pharmaceutical composition of claim 11 or 12 is being prepared for treating and lipid and/or the relevant heart of abnormal carbohydrate metabolism Purposes in the drug of vascular risk factor.
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